Genetic Variant EDA:p.Arg156His (chrX-69957097-G-A) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001399.5(EDA):c.467G>A(p.Arg156His) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,209,437 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.55

Publications

28 publications found

Variant links:

Genes affected

EDA (HGNC:3157): (ectodysplasin A) The protein encoded by this gene is a type II membrane protein that can be cleaved by furin to produce a secreted form. The encoded protein, which belongs to the tumor necrosis factor family, acts as a homotrimer and may be involved in cell-cell signaling during the development of ectodermal organs. Defects in this gene are a cause of ectodermal dysplasia, anhidrotic, which is also known as X-linked hypohidrotic ectodermal dysplasia. Several transcript variants encoding many different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EDA Gene-Disease associations (from GenCC):

tooth agenesis, selective, X-linked, 1
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
X-linked hypohidrotic ectodermal dysplasia
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EDA links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 3 uncertain in NM_001399.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-69957096-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 1.7843 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to tooth agenesis, selective, X-linked, 1, X-linked hypohidrotic ectodermal dysplasia, tooth agenesis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant X-69957097-G-A is Pathogenic according to our data. Variant chrX-69957097-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001399.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDA	NM_001399.5	MANE Select	c.467G>A	p.Arg156His	missense	Exon 2 of 8	NP_001390.1	Q92838-1
EDA	NM_001005609.2		c.467G>A	p.Arg156His	missense	Exon 2 of 8	NP_001005609.1	Q92838-3
EDA	NM_001440761.1		c.467G>A	p.Arg156His	missense	Exon 2 of 8	NP_001427690.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDA	ENST00000374552.9	TSL:1 MANE Select	c.467G>A	p.Arg156His	missense	Exon 2 of 8	ENSP00000363680.4	Q92838-1
EDA	ENST00000374553.6	TSL:1	c.467G>A	p.Arg156His	missense	Exon 2 of 8	ENSP00000363681.2	Q92838-3
EDA	ENST00000524573.5	TSL:1	c.467G>A	p.Arg156His	missense	Exon 2 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112401

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1097036

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362430

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26379

American (AMR)

AF:

0.00

AC:

AN:

35178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19369

East Asian (EAS)

AF:

0.00

AC:

AN:

30149

South Asian (SAS)

AF:

0.00

AC:

AN:

54023

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40501

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841267

Other (OTH)

AF:

0.00

AC:

AN:

46037

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112401

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34579

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30952

American (AMR)

AF:

0.00

AC:

AN:

10665

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2661

East Asian (EAS)

AF:

0.00

AC:

AN:

3554

South Asian (SAS)

AF:

0.00

AC:

AN:

2727

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6131

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53286

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000198

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypohidrotic X-linked ectodermal dysplasia (4)

Ectodermal dysplasia (1)

Hypohidrotic X-linked ectodermal dysplasia;C1970757:Tooth agenesis, selective, X-linked, 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

0.90

PhyloP100

5.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.54

Sift

Uncertain

0.011

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.52

MutPred

0.87

Loss of MoRF binding (P = 0.0444)

MVP

1.0

MPC

0.97

ClinPred

0.82

GERP RS

5.0

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.67

gMVP

0.82

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over